Older adults with perivascular spaces exhibit cerebrovascular reactivity deficits.

BACKGROUND: Perivascular spaces on brain magnetic resonance imaging (MRI) may indicate poor fluid drainage in the brain and have been associated with numerous neurological conditions. Cerebrovascular reactivity (CVR) is a marker of cerebrovascular function and represents the ability of cerebral blood vessels to regulate cerebral blood flow in response to vasodilatory or vasoconstrictive stimuli. We aimed to examine whether pathological widening of the perivascular space in older adults may be associated with deficits in CVR. METHODS: Independently living older adults free of dementia or clinical stroke were recruited from the community and underwent brain MRI. Pseudo-continuous arterial spin labeling MRI quantified whole brain cerebral perfusion at rest and during CVR to hypercapnia and hypocapnia induced by visually guided breathing exercises. Perivascular spaces were visually scored using existing scales. RESULTS: Thirty-seven independently living older adults (mean age = 66.3 years; SD = 6.8; age range 55-84 years; 29.7% male) were included in the current analysis. Multiple linear regression analysis revealed a significant negative association between burden of perivascular spaces and global CVR to hypercapnia (B = -2.0, 95% CI (-3.6, -0.4), p = .015), adjusting for age and sex. Perivascular spaces were not related to CVR to hypocapnia. DISCUSSION: Perivascular spaces are associated with deficits in cerebrovascular vasodilatory response, but not vasoconstrictive response. Enlargement of perivascular spaces could contribute to, or be influenced by, deficits in CVR. Additional longitudinal studies are warranted to improve our understanding of the relationship between cerebrovascular function and perivascular space enlargement.

Cerebrovascular resistance: effects on cognitive decline, cortical atrophy, and progression to dementia.

See Markus (doi:10.1093/awx161) for a scientific commentary on this article.Evidence for vascular contributions to Alzheimer's disease has been increasingly identified, with increased blood pressure and decreased cerebral blood flow both linked to in vivo biomarkers and clinical progression of Alzheimer's disease. We therefore hypothesized that an elevated ratio of blood pressure to cerebral blood flow, indicative of cerebrovascular resistance, would exhibit earlier and more widespread associations with Alzheimer's disease than cerebral blood flow alone. Further, we predicted that increased cerebrovascular resistance and amyloid retention would synergistically influence cognitive performance trajectories, independent of neuronal metabolism. Lastly, we anticipated associations between cerebrovascular resistance and later brain atrophy, prior to amyloid accumulation. To evaluate these hypotheses, we investigated associations between cerebrovascular resistance and amyloid retention, cognitive decline, and brain atrophy, controlling for neuronal metabolism. North American older adults (n = 232) underwent arterial spin labelling magnetic resonance imaging to measure regional cerebral blood flow in brain regions susceptible to ageing and Alzheimer's disease. An estimated cerebrovascular resistance index was then calculated as the ratio of mean arterial pressure to regional cerebral blood flow. Positron emission tomography with 18F-florbetapir and fludeoxyglucose was used to quantify amyloid retention and neuronal metabolism, respectively. Cognitive performance was evaluated via annual assessments of global cognition, memory, and executive function. Results indicated diminished inferior parietal and temporal cerebral blood flow for patients with Alzheimer's disease (n = 33) relative to both non-demented groups, but no cerebral blood flow differences between non-demented amyloid-positive (n = 87) and amyloid-negative (n = 112) cases. In contrast, the cerebrovascular resistance index was significantly elevated in amyloid-positive versus amyloid-negative cases, with additional elevation in patients with Alzheimer's disease. Furthermore, cerebrovascular resistance index group differences were of greater statistical effect size and encompassed a greater number of brain regions than those for cerebral blood flow alone. Cognitive decline over 2-year follow-up was accelerated by elevated baseline cerebrovascular resistance index, particularly for amyloid-positive individuals. Increased baseline cerebrovascular resistance index also predicted greater progression to dementia, beyond that attributable to amyloid-positivity. Finally, increased cerebrovascular resistance index predicted greater regional atrophy among non-demented older adults who were amyloid-negative. Findings suggest that increased cerebrovascular resistance may represent a previously unrecognized contributor to Alzheimer's disease that is independent of neuronal hypometabolism, predates changes in brain perfusion, exacerbates and works synergistically with amyloidosis to produce cognitive decline, and drives amyloid-independent brain atrophy during the earliest stage of disease.

Ventromedial-frontopolar prefrontal cortex atrophy correlates with insight loss in frontotemporal dementia and Alzheimer's disease.

Loss in insight is a major feature of frontotemporal dementia (FTD) but has been investigated relatively little. More importantly, the neural basis of insight loss is still poorly understood. The current study investigated insight deficit profiles across a large cohort of neurodegenerative patients (n = 81), including FTD and Alzheimer's disease (AD) patients. We employed a novel insight questionnaire, which tapped into changes across different domains: social interaction, emotion, diagnosis/treatment, language, and motivation. FTD subtypes varied considerably for insight loss, with the behavioral variant worst and the progressive non-fluent variant least affected. All other subtypes and AD showed milder but consistent insight loss. Voxel-based morphometry analysis revealed that overall insight loss correlated with ventromedial and frontopolar prefrontal atrophy, with exception of social interaction and emotion insight loss, which additionally correlated with lateral temporal and amygdala atrophy, respectively. Our results show that patients with neurodegenerative conditions show variable loss of insight, with ventromedial and frontopolar cortex regions appearing to be particularly important for insight.

Detecting and Predicting Cognitive Decline in Individuals with Traumatic Brain Injury: A Longitudinal Telephone-Based Study.

Traumatic brain injuries (TBIs) can lead to long-lasting cognitive impairments, and some survivors experience cognitive decline post-recovery. Early detection of decline is important for care planning, and understanding risk factors for decline can elucidate targets for prevention. While neuropsychological testing is the gold standard approach to characterizing cognitive function, there is a need for brief, scalable tools that are capable of detecting clinically significant changes in post-TBI cognition. This study examines whether a clinically significant change can be detected using the Brief Test of Adult Cognition by Telephone (BTACT) in a sample of individuals with chronic TBI and investigates whether potentially modifiable factors are associated with cognitive decline. Ninety participants aged 40 or older with complicated mild-to-severe TBI participated in two telephone-based study visits ∼1 year apart. Demographic, head trauma exposure, comorbid medical conditions, physical, and psychosocial functioning data were collected via self-report. The BTACT, a brief measure of global cognitive function, was used to assess cognitive performance across six domains. A reliable change index for quantifying clinically significant changes in BTACT performance was calculated. Results revealed cognitive decline in 10-27% of participants across various cognitive domains. More specifically, only depressive symptoms, including depressed affect and anhedonia, were significantly associated with cognitive decline after correcting for multiple comparisons using false discovery rate (FDR). Other factors such as the number of blows to the head, male gender, dyspnea, increased anxiety symptoms, seizures, illicit drug use, and fewer cardiovascular comorbidities should be considered hypothesis generating. Importantly, age was not a significant predictor of cognitive decline, which challenges the assumption that cognitive decline is solely related to the natural aging process. It suggests that there are unique factors associated with TBI that impact cognitive function, and these factors can affect individuals across the lifespan. The BTACT is a brief and sensitive tool for identifying clinically meaningful changes in cognitive function over a relatively brief period (i.e., 1 year) in a sample of individuals in the chronic stages of TBI (i.e., x̄ = 6.7 years post-TBI). Thus, the BTACT may be useful in surveillance efforts aimed at understanding and detecting decline, particularly in situations where in-person cognitive screening is impractical or unfeasible. We also identified potentially modifiable targets for the prevention of post-TBI cognitive decline. These findings can offer insights into treatment goals and preventive strategies for individuals at risk for cognitive decline, as well as help to facilitate early identification efforts.

Blood-Derived Progenitor Cells Are Depleted in Older Adults with Cognitive Impairment: A Role for Vascular Resilience?

BACKGROUND: Depletion of blood-derived progenitor cells, including so called "early endothelial progenitor cells", has been observed in individuals with early stage Alzheimer's disease relative to matched older control subjects. These findings could implicate the loss of angiogenic support from hematopoietic progenitors or endothelial progenitors in cognitive dysfunction. OBJECTIVE: To investigate links between progenitor cell proliferation and mild levels of cognitive dysfunction. METHODS: We conducted in vitro studies of blood-derived progenitor cells using blood samples from sixty-five older adults who were free of stroke or dementia. Peripheral blood mononuclear cells from venous blood samples were cultured in CFU-Hill media and the number of colony forming units were counted after 5 days in vitro. Neuropsychological testing was administered to all participants. RESULTS: Fewer colony forming units were observed in samples from older adults with a Clinical Dementia Rating global score of 0.5 versus 0. Older adults whose samples developed fewer colony forming units exhibited worse performance on neuropsychological measures of memory, executive functioning, and language ability. CONCLUSION: These data suggest blood progenitors may represent a vascular resilience marker related to cognitive dysfunction in older adults.

Older Adults With Higher Blood Pressure Variability Exhibit Cerebrovascular Reactivity Deficits.

BACKGROUND: Elevated blood pressure (BP) variability is predictive of increased risk for stroke, cerebrovascular disease, and other vascular brain injuries, independent of traditionally studied average BP levels. However, no studies to date have evaluated whether BP variability is related to diminished cerebrovascular reactivity, which may represent an early marker of cerebrovascular dysfunction presaging vascular brain injury. METHODS: The present study investigated BP variability and cerebrovascular reactivity in a sample of 41 community-dwelling older adults (mean age 69.6 [SD 8.7] years) without a history of dementia or stroke. Short-term BP variability was determined from BP measurements collected continuously during a 5-minute resting period followed by cerebrovascular reactivity during 5-minute hypocapnia and hypercapnia challenge induced by visually guided breathing conditions. Cerebrovascular reactivity was quantified as percent change in cerebral perfusion by pseudo-continuous arterial spin labeling (pCASL)-MRI per unit change in end-tidal CO2. RESULTS: Elevated systolic BP variability was related to lower whole brain cerebrovascular reactivity during hypocapnia (ß = -0.43 [95% CI -0.73, -0.12]; P = 0.008; adjusted R2 =.11) and hypercapnia (ß = -0.42 [95% CI -0.77, -0.06]; P = 0.02; adjusted R2 = 0.19). CONCLUSIONS: Findings add to prior work linking BP variability and cerebrovascular disease burden and suggest BP variability may also be related to prodromal markers of cerebrovascular dysfunction and disease, with potential therapeutic implications.

Enlarged perivascular spaces and plasma Aß42/Aß40 ratio in older adults without dementia.

Dilation of perivascular spaces (PVS) in the brain may indicate poor fluid drainage due to the accumulation of perivascular cell debris, waste, and proteins, including amyloid-beta (Aß). No prior study has assessed whether plasma Aß levels are related to PVS in older adults without dementia. Independently living older adults (N = 56, mean age = 68.2 years; Standard deviation (SD) = 6.5; 30.4% male) free of dementia or clinical stroke were recruited from the community and underwent brain MRI and venipuncture. PVS were qualitatively scored and dichotomized to low PVS burden (scores 0-1,) or high PVS burden (score>1). Plasma was assayed using a Quanterix Simoa Kit to quantify Aß42 and Aß40 levels. A significant difference was observed in plasma Aß42/Aß40 ratio between low and high PVS burden, controlling for age (F[1, 53] = 5.59, p = 0.022, η2 = 0.10), with lower Aß42/Aß40 ratio in the high PVS burden group. Dilation of PVS is associated with a lower plasma Aß42/Aß40 ratio, which may indicate higher cortical amyloid deposition. Future longitudinal studies examining PVS changes, and the pathogenesis of AD are warranted.

Cerebrovascular reactivity deficits in cognitively unimpaired older adults: vasodilatory versus vasoconstrictive responses.

Cerebrovascular reactivity (CVR) deficits may index vulnerability to vascular brain injury and cognitive impairment, but findings on age-related changes in CVR have been mixed, and no studies to date have directly compared age-related changes in CVR to hypercapnia versus hypocapnia. The present study compared CVR in 31 cognitively unimpaired older adults (ages 55-87) and 30 healthy younger adults (ages 18-28). Breath control tasks induced CVR to hypocapnia (0.1 Hz paced breathing) and hypercapnia (15s breath holds) during pseudo-continuous arterial spin labeling MRI. Relative to younger adults, cognitively unimpaired older adults displayed lower levels of global CVR under both hypocapnia and hypercapnia. In region-of-interest analyses, older adults exhibited attenuated CVR to hypocapnia in select frontal and temporal regions, and lower CVR to hypercapnia in all cortical, limbic, and subcortical regions examined, relative to younger adults. Results indicate age-related deficits in CVR are detectible even in cognitively unimpaired older adults and are disproportionately related to vasodilatory (hypercapnia) responses relative to vasoconstrictive (hypocapnia) responses. Findings may offer means for early detection of cerebrovascular dysfunction.

Changes in alcohol use and mood during the COVID-19 pandemic among individuals with traumatic brain injury: A difference-in-difference study.

OBJECTIVE: To evaluate the impact of COVID-19 pandemic exposure on changes in alcohol use and mood from years 1 to 2 after traumatic brain injury (TBI). METHODS: We used a difference-in-difference (DiD) study design to analyze data from 1,059 individuals with moderate-to-severe TBI enrolled in the TBI Model Systems (TBIMS) National Database. We defined COVID-19 pandemic exposure as participants who received their year 1 post-injury interviews prior to January 1, 2020, and their year 2 interview between April 1, 2020 and January 15, 2021. Pandemic-unexposed participants had both year 1 and 2 follow-up interviews before January 1, 2020. We measured current alcohol use as any past month alcohol use, average number of drinks per drinking occasion, and past month binge drinking. We measured depression symptoms using Patient Health Questionnaire-9, and anxiety symptoms using the Generalized Anxiety Disorder-7. RESULTS: We found persons with TBI exposed to the pandemic had greater increases in the average number of drinks per occasion from year 1 to 2 post-injury compared to pandemic-unexposed individuals (ß = 0.36, 95% CI: 0.16, 0.57, p = 0.001), with males, adults <65 years old, and Black and Hispanic subgroups showing the greatest increases in consumption. Though average consumption was elevated, changes in rates of any alcohol use or binge drinking by pandemic exposure were not observed. Overall, there were no significant changes in depressive and anxiety symptoms over time between pandemic exposed and unexposed groups; however, pandemic-exposed Hispanics with TBI reported significant increases in anxiety symptoms from year-1 to year-2 post-injury compared to pandemic-unexposed Hispanics (ß = 2.35, 95% CI: 0.25, 4.47, p = 0.028). CONCLUSION: Among persons living with TBI, those exposed to the pandemic had significant increases in average alcohol consumption. Pandemic-exposed Hispanics with TBI had large elevations in anxiety symptoms, perhaps reflecting health inequities exacerbated by the pandemic, and suggesting a need for targeted monitoring of psychosocial distress.

Selective vulnerability of medial temporal regions to short-term blood pressure variability and cerebral hypoperfusion in older adults.

Blood pressure variability is an emerging risk factor for stroke, cognitive impairment, and dementia, possibly through links with cerebral hypoperfusion. Recent evidence suggests visit-to-visit (e.g., over months, years) blood pressure variability is related to cerebral perfusion decline in brain regions vulnerable to Alzheimer's disease. However, less is known about relationships between short-term (e.g., < 24 hours) blood pressure variability and regional cerebral perfusion, and whether these relationships may differ by age. We investigated short-term blood pressure variability and concurrent regional cerebral microvascular perfusion in a sample of community-dwelling older adults without history of dementia or stroke and healthy younger adults. Blood pressure was collected continuously during perfusion MRI. Cerebral blood flow was determined for several brain regions implicated in cerebrovascular dysfunction in Alzheimer's disease. Elevated systolic blood pressure variability was related to lower levels of concurrent cerebral perfusion in medial temporal regions: hippocampus (ß = -.60 [95% CI -.90, -.30]; p < .001), parahippocampal gyrus (ß = -.57 [95% CI -.89, -.25]; p = .001), entorhinal cortex (ß = -.42 [95% CI -.73, -.12]; p = .009), and perirhinal cortex (ß = -.37 [95% CI -.72, -.03]; p = .04), and not in other regions, and in older adults only. Findings suggest a possible age-related selective vulnerability of the medial temporal lobes to hypoperfusion in the context of short-term blood pressure fluctuations, independent of average blood pressure, white matter hyperintensities, and gray matter volume, which may underpin the increased risk for dementia associated with elevated BPV.

Blood pressure variability and plasma Alzheimer's disease biomarkers in older adults.

Blood pressure variability is an emerging risk factor for Alzheimer's disease in older adults, independent of average blood pressure levels. Growing evidence suggests increased blood pressure variability is linked to Alzheimer's disease pathophysiology indexed by cerebrospinal fluid and positron emission tomography markers, but relationships with plasma Alzheimer's disease markers have not been investigated. In this cross-sectional study of 54 community-dwelling older adults (aged 55-88, mean age 69.9 [8.2 SD]), elevated blood pressure variability over 5 min was associated with lower levels of plasma Aß1-42 (standardized ß = - 0.36 [95% CI - 0.61, - 0.12]; p = 0.005; adjusted R2 = 0.28) and Aß1-42: Aß1-40 ratio (ß = - 0.49 [95% CI - 0.71, - 0.22]; p < 0.001; adjusted R2 = 0.28), and higher levels of total tau (ß = 0.27 [95% CI 0.01, 0.54]; p = 0.04; adjusted R2 = 0.19) and Ptau181:Aß1-42 ratio (ß = 0.26 [95% CI 0.02, 0.51]; p = 0.04; adjusted R2 = 0.22). Findings suggest higher blood pressure variability is linked to plasma biomarkers of increased Alzheimer's disease pathophysiology.

Visit-to-visit blood pressure variability and regional cerebral perfusion decline in older adults.

Blood pressure variability (BPV) is linked to dementia risk, possibly through cerebral hypoperfusion. We investigated BPV over 1 year and concurrent regional cerebral perfusion decline in older adults without dementia. Participants underwent 4 blood pressure measurements across 12 months, ASL-MRI at baseline and 12-months, and baseline FDG-PET. Regional perfusion was normalized to precentral gyrus. A subset had cerebral spinal fluid Alzheimer's disease biomarker abnormalities. For every SD increase in BPV, perfusion decreased in medial orbitofrontal cortex (ß = -.36; p = 0.008), hippocampus (ß = -.37; p = 0.005), entorhinal cortex (ß = -.48; p < 0.001), precuneus (ß = -.31; p = 0.02), inferior parietal cortex (ß = -.44; p < 0.001), and inferior temporal cortex (ß = -.46; p < 0.001). Similar patterns emerged in subsets with biomarker abnormalities. Older adults with elevated BPV exhibit concurrent regional perfusion decline in areas vulnerable to Alzheimer's disease, independent of cerebral hypometabolism. BPV may be an early marker of vascular dysfunction in aging.

Resting-State Functional Connectivity Signatures of Apathy in Community-Living Older Adults.

Apathy predicts poor outcomes in older adults, and its underlying neural mechanism needs further investigation. We examined the association between symptoms of apathy and functional connectivity (FC) in older adults without stroke or dementia. Participants included 48 individuals (mean age = 70.90) living independently in the community, who underwent resting-state fMRI and completed the Apathy Evaluation Scale (AES). Seed-to-voxel analysis (cluster-level p-FDR <0.05, voxel threshold p < 0.001) tested the association between AES scores and the whole-brain FC of brain regions involved in reward- and salience-related processing. We found that AES scores were negatively associated with FC of the right insula cortex and right anterior temporal regions (124 voxels, t = -5.10) and FC of the left orbitofrontal cortex and anterior cingulate regions (160 voxels, t = -5.45), and were positively associated with FC of the left orbitofrontal cortex and left lateral prefrontal (282 voxels, t = 4.99) and anterior prefrontal (123 voxels, t = 4.52) regions. These findings suggest that apathy in older adults may reflect disruptions in neural connectivity involved in reward- and salience-related processing.

Increased Levels of Circulating Angiogenic Cells and Signaling Proteins in Older Adults With Cerebral Small Vessel Disease.

Background: Cerebral small vessel disease (SVD) is associated with increased risk of stroke and dementia. Progressive damage to the cerebral microvasculature may also trigger angiogenic processes to promote vessel repair. Elevated levels of circulating endothelial progenitor cells (EPCs) and pro-angiogenic signaling proteins are observed in response to vascular injury. We aimed to examine circulating levels of EPCs and proangiogenic proteins in older adults with evidence of SVD. Methods: Older adults (ages 55-90) free of dementia or stroke underwent venipuncture and brain magnetic resonance imaging (MRI). Flow cytometry quantified circulating EPCs as the number of cells in the lymphocyte gate positively expressing EPC surface markers (CD34+CD133+CD309+). Plasma was assayed for proangiogenic factors (VEGF-A, VEGF-C, VEGF-D, Tie-2, and Flt-1). Total SVD burden score was determined based on MRI markers, including white matter hyperintensities, cerebral microbleeds and lacunes. Results: Sixty-four older adults were included. Linear regression revealed that older adults with higher circulating EPC levels exhibited greater total SVD burden [ß = 1.0 × 105, 95% CI (0.2, 1.9), p = 0.019], after accounting for age and sex. Similarly, a positive relationship between circulating VEGF-D and total SVD score was observed, controlling for age and sex [ß = 0.001, 95% CI (0.000, 0.001), p = 0.048]. Conclusion: These findings suggest that elevated levels of circulating EPCs and VEGF-D correspond with greater cerebral SVD burden in older adults. Additional studies are warranted to determine whether activation of systemic angiogenic growth factors and EPCs represents an early attempt to rescue the vascular endothelium and repair damage in SVD.

Circulating Progenitor Cells Correlate with Memory, Posterior Cortical Thickness, and Hippocampal Perfusion.

BACKGROUND: Bone marrow-derived progenitor cells survey the vasculature and home to sites of tissue injury where they can promote repair and regeneration. It has been hypothesized that these cells may play a protective role neurodegenerative and vascular cognitive impairment. OBJECTIVE: To evaluate progenitor cell levels in older adults with and without mild cognitive impairment (MCI), and to relate circulating levels to memory, brain volume, white matter lesion volume, and cerebral perfusion. METHOD: Thirty-two older adults, free of stroke and cardiovascular disease, were recruited from the community and evaluated for diagnosis of MCI versus cognitively normal (CN). Participants underwent brain MRI and blood samples were taken to quantify progenitor reserve using flow cytometry (CD34+, CD34+CD133+, and CD34+CD133+CD309+ cells). RESULTS: Participants with MCI (n = 10) exhibited depletion of all CPC markers relative to those who were CN (n = 22), after controlling for age, sex, and education. Post-hoc age, sex, and education matched comparisons (n = 10 MCI, n = 10 CN) also revealed the same pattern of results. Depletion of CD34+ cells correlated with memory performance, left posterior cortical thickness, and bilateral hippocampal perfusion. Participants exhibited low levels of vascular risk and white matter lesion burden that did not correlate with progenitor levels. CONCLUSIONS: Circulating progenitor cells are associated with cognitive impairment, memory, cortical atrophy, and hippocampal perfusion. We hypothesize that progenitor depletion contributes to, or is triggered by, cognitive decline and cortical atrophy. Further study of progenitor cell depletion in older adults may benefit efforts to prevent or delay dementia.

Older Adults Taking AT1-Receptor Blockers Exhibit Reduced Cerebral Amyloid Retention.

BACKGROUND: Evidence suggests that angiotensin II AT1-receptor blockers (ARBs) may be protective against dementia, and studies in transgenic animals indicate that this may be due to improved amyloid-ß (Aß) clearance. OBJECTIVE: We investigated whether taking ARBs was associated with an attenuation of age-related increases in cerebral Aß retention, and reduced progression to dementia. METHODS: Eight hundred seventy-one stroke-free and dementia-free older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study underwent baseline lumbar puncture, and a subgroup (n = 124) underwent 12 and 24 month follow-up lumbar puncture. Participants were followed at variable intervals for clinical progression to dementia. Linear mixed models and ANCOVA compared ARBs users with those taking other antihypertensives (O-antiHTN) or no antihypertensives (No-antiHTN) on cerebrospinal fluid (CSF) Aß and phosphorylated tau (P-tau) levels. Cox regression and chi-square analyses compared groups on progression to dementia. RESULTS: ARBs users exhibited greater vascular risk and lower educational attainment than the No-antiHTN group. Longitudinal analyses indicated higher CSF Aß and lower P-tau in ARBs users versus other groups. Cross-sectional analyses revealed age-related decreases in CSF Aß in other groups but not ARBs users. ARBs users were less likely to progress to dementia and showed reduced rate of progression relative to the No-antiHTN group. DISCUSSION: Patients taking ARBs showed an attenuation of age-related decreases in CSF Aß, a finding that is consistent with studies done in transgenic animals. These findings may partly explain why ARBs users show reduced progression to dementia despite their lower educational attainment and greater vascular risk burden.

A visual MRI atrophy rating scale for the amyotrophic lateral sclerosis-frontotemporal dementia continuum.

Our objective was to distinguish ALS, ALS-FTD and bvFTD via a novel visual MRI cortical atrophy scale that can be employed in a clinical setting. MRI images of 100 participants (33 ALS, 11 ALS-FTD, 22 bvFTD and 34 controls) were rated in four brain areas: orbitofrontal cortex, anterior temporal pole, anterior cingulate, and motor cortex. Areas were rated on a 5- point Likert scale by two raters blinded to the diagnosis. Results demonstrated that bvFTD patients showed the highest levels of atrophy across all regions, while ALS patients had the lowest atrophy scores. ALS-FTD patients have higher atrophy ratings compared to ALS patients for the motor cortex, anterior cingulate and anterior temporal lobe, with a statistical trend for the orbitofrontal cortex. ALS-FTD patients were not significantly different from bvFTD for any of the brain regions. These findings were confirmed in a post hoc VBM analysis of the same participants. Our study demonstrates that a simple visual MRI rating scale can reliably distinguish ALS, ALS-FTD and bvFTD atrophy patterns in a clinical setting. Motor cortex, anterior cingulate and anterior temporal atrophy emerged as good diagnostic markers for ALS-FTD. Employment of this MRI rating scale can complement clinical diagnostics of patients in the ALS-FTD continuum.

Longitudinal grey and white matter changes in frontotemporal dementia and Alzheimer's disease.

Behavioural variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) dementia are characterised by progressive brain atrophy. Longitudinal MRI volumetry may help to characterise ongoing structural degeneration and support the differential diagnosis of dementia subtypes. Automated, observer-independent atlas-based MRI volumetry was applied to analyse 102 MRI data sets from 15 bvFTD, 14 AD, and 10 healthy elderly control participants with consecutive scans over at least 12 months. Anatomically defined targets were chosen a priori as brain structures of interest. Groups were compared regarding volumes at clinic presentation and annual change rates. Baseline volumes, especially of grey matter compartments, were significantly reduced in bvFTD and AD patients. Grey matter volumes of the caudate and the gyrus rectus were significantly smaller in bvFTD than AD. The bvFTD group could be separated from AD on the basis of caudate volume with high accuracy (79% cases correct). Annual volume decline was markedly larger in bvFTD and AD than controls, predominantly in white matter of temporal structures. Decline in grey matter volume of the lateral orbitofrontal gyrus separated bvFTD from AD and controls. Automated longitudinal MRI volumetry discriminates bvFTD from AD. In particular, greater reduction of orbitofrontal grey matter and temporal white matter structures after 12 months is indicative of bvFTD.

Lost and forgotten? Orientation versus memory in Alzheimer's disease and frontotemporal dementia.

Recent studies suggest that significant memory problems are not specific to Alzheimer's disease (AD) but can be also observed in other neurodegenerative conditions, such as behavioral variant frontotemporal dementia (bvFTD). We investigated whether orientation (spatial & temporal) information is a better diagnostic marker for AD compared to memory and whether their atrophy correlates of orientation and memory differ. A large sample (n = 190) of AD patients (n = 73), bvFTD patients (n = 54), and healthy controls (n = 63) underwent testing. A subset of the patients (n = 72) underwent structural imaging using voxel-based morphometry analysis of magnetic resonance brain imaging. Orientation and memory scores from the Addenbrooke's Cognitive Examination showed that AD patients had impaired orientation and memory, while bvFTD patients performing at control level for orientation but had impaired memory. A logistic regression showed that 78% of patients could be classified on the basis of orientation and memory scores alone at clinic presentation. Voxel-based morphometry analysis was conducted using orientation and memory scores as covariates, which showed that the neural correlates for orientation and memory also dissociated with posterior hippocampus cortex being related to orientation in AD, while the anterior hippocampus was associated with memory performance in the AD and bvFTD patients. Orientation and memory measures discriminate AD and bvFTD to a high degree and tap into different hippocampal regions. Disorientation and posterior hippocampus appears therefore specific to AD and will allow clinicians to discriminate AD patients from other neurodegenerative conditions with similar memory deficits at clinic presentation.

Cortical atrophy in ALS is critically associated with neuropsychiatric and cognitive changes.

OBJECTIVE: To characterize the patterns of brain atrophy in patients with amyotrophic lateral sclerosis (ALS) with and without cognitive and neuropsychiatric symptoms, in comparison to controls and patients with ALS-frontotemporal dementia (FTD). METHODS: A total of 57 participants (ALS = 22; ALS-FTD = 17; controls = 18) were included, following current ALS and FTD criteria. Patients with ALS were further subclassified into ALS with cognitive and behavioral symptoms (ALS-plus; n = 8) and those without (ALS; n = 14). By definition, ALS-plus did not reach the diagnostic threshold for ALS-FTD. All patients underwent neuropsychological and neuropsychiatric assessments, and underwent a brain MRI. Voxel-based morphometry analysis was conducted to establish patterns of brain atrophy. RESULTS: Cortical atrophy in ALS was linked to neuropsychiatric and cognitive changes (ALS-plus vs ALS). Patients with ALS-plus had significant atrophy across motor and somatosensory as well as adjacent frontal and parietal areas, even after strict multiple comparison correction. By contrast, patients with ALS showed no significant cortical atrophy, and only brainstem atrophy. Importantly, atrophy in ALS-plus was not as widespread as in ALS-FTD, with ALS-plus atrophy mostly confined to motor and somatosensory areas, while atrophy in ALS-FTD also included substantial frontal and temporal atrophy. CONCLUSIONS: The present findings establish that cortical atrophy in ALS is highly dependent upon neuropsychiatric and cognitive changes. Previous inconsistent findings of cortical atrophy in ALS likely relate to the inclusion of cognitively affected patients and patients with pure motor ALS.